Growth promotant substances



United States Patent 3,085,933 GROWTH PROMOTANT SUBSTANCES Maurice A. Schooley and Byron M. Shinn, Western Springs, 111., assignors, by mesne assignments, to Armour & Company, Chicago, Ill, a corporation of Delaware No Drawing. Filed Oct. 3, 1958, Ser. No. 765,045 14 Claims. (Cl.16753) This invention relates to a novel composition which is useful as a growth promotant. More particularly this invention relates to an improved growth promoting factor comprising a combination of an estrogenic substance and a salt of a cationic surfactant.

It has been found that a number of so-called growth promoting substances when introduced into an'animal either orally, by skin implantation, or otherwise, result in accelerated growth of the animal. Perhaps the best established of these substances are certain growth-stimulating antibiotics such as, for example, aureomycin. Since these substances apparently are not a normal nutritional requirement of animals, it is believed that their principal effect is to suppress diseases of the animals including those subclinical diseases which are not manifest. Animal-s .thus treated, therefore, are more healthy and will tend to. grow and gain weight at an increased rate.

In addition, as reported in the literature in this field, there are indications that other non-nutritional substances, principally surfactants, under certain conditions may also stimulate growth. It has been postulated that the growth promoting properties of surfactants may be related to their bactericidal and basteriostatic characteristics, and that, therefore, their action is similar tofthat of the antibiotics.

Another class of substances which fall within the category of growth promotants are estrogenic compounds. The growth and weight aceclerating' advantages of these substances has made their use desirable and profitable even though it has been recognized that their use presents certain inherent difficulties and hazards. One of the problems encountered in the livestock industry, for exam ple, in employing estrogenic substances alone as a growth promotant has been the fact that in many instances their use will result in a downgrading of an animal into which they are introduced. The downgrading may occur to such an extent'that even though more pounds of edible flesh are produced for each dollar invested in the raising of theanimal, the total'economic return from the sale of the'animal for food purposes actually will be less than that received from animals which have not been treated with theestrogenic substance; Generally, this eifect has dictatedthat the estrogensbe introducedinto animals at sufficiently low levels to reduce the problemof downgrading. However, at the lower levelsthe growth promotingresults achieved may be substantially reduced.

Still another problem'in' the use of estrogenic substances arises in connection withtheir implantation in livestock destined for themarket place. When thus introduced intoan animal, some ofthe estrogenic material may remain in the edibleportions of the animal, and, if suchis the case, when ulti'matelyconsumed could produce an adverse effect in an individual.

It can be seen from this that it would be desirable to diminish the disadvantages encountered in the use of estrogenic substances-without adversely affecting their growth promoting properties. Viewed in a different light, it would alsobe worth while if these disadvantages could be reduced and the growth promoting-properties of the estrogenic substances maintained or even enhanced. We

have discovered that these objects can be accomplished through the use of a combination of an estrogenic sub- 3,085,933 Patented Apr. 16, 19 63 stance and a salt of a cationic surfactant. The-net result of this combination is an increased feed efii'ciency and promotion of growth in animals into which it is introduced. r

In accordance with the present invention, certainclasses of surfactants which have been chemically modified so as to display substantially'nosurface activity in water,

when combined with a minor amount of an estrogenicsubstance, demonstrate superior growth promoting properties while at the same time eliminating the disadvantages resulting from the use of the estrogenic substance alone.

The'mechanism ofi the'action ofthis combination has not been elucidated, but the net effect is demonstratable and pronounced.

Whilea vraiety of active estrogenic substances may beemployed to achieve the advantages of this inventi'omthe stilbene derivatives are particularly suited. These pre ferred derivatives include such compounds as-diethylstilbestrol, dienestrol, hexestrol; their lower alkyl ethers such as dianisylhexene, dianisylhexadiene and dianisylhexane; and esters such as dienestrol diacetate. Also contemplated by this invention are estrogen derivatives such as those comprising 4,4-oxygenated stilbenederivatives or'4,4'-oxygenated diphenylhexane derivatives, said derivatives having at least two substituents in the aromatic nuclei, the substituents being madeup of aliphatic straight chains containing at least two carbon atoms, branch chains, aromatic rings, and cyclic and heterocyclic rings.

Specific examples of this last mentioned class of estrogen The general class of modified surfactants having utilityfor the purpose of this invention can be designated as the: substantially water-insoluble reaction product ofthe cat ionic fragment of a cationic surfactant with the anionic fragment of either an anionic surfactant or an anionic polyelectrolyte. The cationic fragment of theseagrowth promotant materials may be derived from surface active quaternary ammonium salts, such as the alkyltrimethylammonium halides, dialkyldimethyl-ammoniurn halides, trialkylmethylammonium halides, wherein the alkyl group (or groups) can contain from 8 to 22 carbon atoms and Insteadzof an alkyl can be saturated or unsaturated. groupof the characterde'scribed, .the surfaceactive quaternary ammonium compound cancontain an'aromatic group, such as the benzyl group, and thus the cationic fragment of this reaction product can be obtained from.

such compounds as alkylbenzyldimethylam-monium halides. surfactants from which this cationic fragment can 'be derived as dimethyldidodecylammonium chloride, trimethyldodecylannnonium chloride, dimethyldioctadecylam monium chloride, trimethyloctadecylammoniumchloride, dodecyldirnethylbenzylammonium chloride,. octadecyldimethyl-benzylamrnonium chloride, (.p-diisobutylphenoxyethoxy)ethylbenzenedimethylammonium chloride, trimethyloctylammoniurn chloride, dimethyldodecylbenzyl ammonium chloride and methyltrioctadecylammonium1 chloride. Also, mixtures of different cationic surfactants can be employed, such as the naturaltoccum'ng: mixtures where the quaternary ammonium compound. is prepared from a natural fatty acid source. 'For example trimethylcocoammonium chloride, dimethy1ditallowammonium chloride, trimethylsoyaammonium chloride,.etc.,

are. suitable sources for the cationic fragment of this reaction product. This cationic frag'mentmay also be We mention, for example, such specific cationic.

derived from surface active primary, secondary and tertiary amines, such as alkylamines, dialkylamines, dimethylalkylamines, bis(2-hydroxyethyl) alkylamines and N-alkyLLB-propanediamines, wherein the amines contain at least one alkyl chain having from 8 to 22 carbon atoms. By way of specific example, we mention such suitable amines as octadecylamine, dimethyloctadecylamine, bis(2- hydroxyethyl)octadecylamine, methyldioctadecylamine, dioctadecylamine, dimethyldodecylamine, and N-dodecyl- 1,2-propanediamine. Further, polyamines, such as N- dodecyltrimethylenediamine and cyclic nitrogen compounds such as l-alkylpyridinium halides, for example 1- octadecylpyridinium chloride, can be employed to derive the cationic fragment of this reaction product.

The anionic fragment of the substantially water-insoluble pyrolelectrolyte derivatives of the cationic surfactants having utility for the purpose of this invention may be derived from any anionic polyelectrolyte, such as polysulfonic acids, e.g., a hexasulfonic acid (Suramin) and polysulfonic acid resins (Amber-lite IR-IOS); non-polymeric polysulfonic acids, e.g. acidic azo-dye such as Trypan Red and Direct Blue BB; polysulfuric esters, e.g. agar agar and carragheen mucilage; polycarboxylic acids; e.g. polyacrylic acid, weak cation exchange resins, arabic acid, alginic acid, pectic acid; polysaccharinic acids such as carboxymethylcellulose, oxidized starch, mucin, hyaluronic acid, polyglucuronic acid, and acids derived from naturally occurring gums such as tragacanth, locust bean, quince seed, linseed, karaya and acacia; mixed polycarboxylic acids and polysulfuric acid esters, e.g. heparin and chondroitin sulfuric acids; polyphosphonic acids, e.g. Duolite C-6l; polyphosphoric acid esters, e.g. Duolite C65 and phytic acid (hexaphosphoric acid ester); and polysilicates, e.g. bentonite.

The anionic fragment of the substantially water-insoluble anionic surfactant derivatives of the cationic surfactants contemplated by this invention may be derived from such compounds as fatty acids and soaps, i.e. sodium or potassium salts of a higher fatty acid, e.g. sodium stearate, potassium oleate, potassium octanoate, sodium decanoate, sodium laurate or other salts of fatty acids containing from 8 to 22 carbon atoms in which the hydrocarbon chains are either saturated or unsaturated. Also, this anionic fragment can be derived from such synthetic anionic surfactants as alkyl sulfates, alkyl sulfonates, alkyl aryl sulfonates and dialkyl sulfosuccinates. Further, such surface active compounds as cyclic acids, e.g. abietic and cholic, and acyl methyl taurides may be employed in producing this anionic fragment of the reaction product.

By way of specific example of the type of synthetic anionic surfactants useful in forming the compounds of this invention, we mention dodecylsulfate, octadecylbenzenesodium sulfate, the ester of oleic acid, and hydroxy ethane sodium sulfonate.

In practicing this invention, the derivative of the cationic surfactant may be combined with the estrogenic substance merely by mixing them together in suitable proportions. It has been found that the range of concentration of the components of the combination is rather wide. Relatively small amounts of the active ingredients, for example, may be incorporated into nutrient materials, such as an animal feed or water, and still produce a highly desirable result in a short period of time.

Suitable carriers may be employed in the preparation of concentrates containing the combination of active ingredients. Examples of such carriers are soybean oil meal, cottonseed oil meal, and linseed oil meal. Bone meal also may be employed as a diluent when the combination is used for animal feeding purposes. The carrier facilitates uniform distribution of the active agents in the nutrient material with which the concentrates are blended.

The combination may advantageously be administered orally to both animals and humans as a tablet, capsule, suspension, etc. Skin implants are also contemplated for Table I Lot Treatment DES, DES, TAS, TAS TAS Con 36 mg. 10 mg. eon- D E S, D ES, trol implant daily trol 36 mg. 10 mg.

implant daily No. steers j 13 12 13 13 12 12 599 595 606 605 575 880 889 880 925 866 290 294 274 320 201 2. 59 2. 63 2. 45 2. 2.60

Table II Lot Treatment DES, DES, TAS, TAS TAS Con- 18 mg. 24 mg. eon- DES, DES, trol implant implant trol 18 mg. 24 mg.

impl. lmpl.

594 595 587 581 572 587 740 754 763 746 773 782 ain 146 159 176 201 Daily gain 1. 75 1. 89 2. l0 1. 96 2. 40 2. 33

TAS led at rate of 1.5 grams/head/day (steers and heifers).

Ration hand fed as follows:

% rolled barley dried molasses beet pulp Grass hay roughage 1# 32% protein supplement pellets as follows:

The steers in lot 5 receiving TAS and DES implants gained 22% more than controls, and 10% more than those implanted with DES alone. The heifers showed a similar pattern for this class of animals.

EXAMPLE II Employing a slightly different ration from that of Example I, and a different level of TAS under feed lot conditions, the complementary effect of the combination of TAS and DES produced the results tabulated below:

Group 1 Group 2 Group 3 Group 4 36 mg. TAS-+36 Control DES 2 g. TAS mg. DES

implant No. steers 20 20 2O 20 619 616 606 610 018 973 958 976 101 101 101 101 2. 97 3. 54 3. 48 3. 63

Ration: Percent Barley 45 Cull peas 17 Cut pulp 75 Cane molasses 5 Salt .015

Alfalfa 25 TASalone .(group: 3) gave- 21 0.51 pound per :"h'ead lper day increase over the controls. DES alone:.(group12) gave a 0.57 pound. increase whereasthe-combination (group 4) increased gains 0.66 pound per head 'perday.

EXAMPLE III Under field conditions in the summer months, the advantages of the combination of TAS andDESwere shown as follows:

Lot 110 Lot 210 mg.DES mg. DES

daily daily, 1 gram 'IAS daily No. steers 19 19 Av. starting wt; 731 742 Av. final wt 1,080 1,136 Gain/steer 349 394 Av. daily gain (May 12Aug. 31) 3. 14 3. 55

Ration: ll6-32% protein supplement/head/day. Roughage:

Corn silage, alfalfa hay, 2 lbs. dried beet pulp plus grain mixture Percent Corn 25 Wheat 50 Barley 25 EXAMPLE IV The same pattern as in the preceding examples was shown with a larger number of animals as follows:

Employing a ration high in concentrates and self feeding the following results were obtained in a 160 day study:

36 mg. DES 36 mg. DES implant implant 200 g.

TAS/ton feed No. animals 14 12 704 708 1114 1157 2. 79 3.10 24.4 28.2 875 908 3. 57 4. 36 60. 90 62. 71 657.7 710.8 28.15 29. 51 304.07 334. 51

Av. carcass grade:

Choice 1 4 Choice... 4 5 Choice 4 1 Good 2 0 Good 1 0 Ration: Percent Rolled shelled corn 67.5 Soybean oil meal 10.0 Ground alfalfa hay 20.0 Bone meal 1.5 Trace mineral salt 1.0

EXAMPLE v1 Employing .the same .selifi :fe'eding techniques as in Ex. ample V but using an all pelleted'ration the following'1 12 day results in" steers were-obtained:

LotNo; l 1' 2 3 4- 5 Treatment: 3

Se1f'fe'd X, X X- X X Completed pelletedratiom. 0 X X X Y X Allaliahay long X 0 0 I O I 0 Strawad lib 0-. 0 X 1 X X TAS 200 g./t0n 0 0 0 X X DES implants, 36 0 0 0 0 X No; steers 8 8 8 8 8 Initial wt; 527 520 511 526 526 Final-wt. 861.- 832. 858 s 916 Av; daily gain 2.98 2. 84 3.09 3.25 3.49.

Composition of pelleted ration I Percent Barley 40 Beef pulp-OM l 20 Alfialfa'. ground .1... 30 Wheat mixed feed 5 Molasses: 5

EXAMPLE VII Finallythe. eifeots of .TAS' alone, DESna-lone zand xthe conibinationwoffthe 'two drugs were tested in i steer scalves on a constant intake of -a wintering ration, as follows:

In preparing the animal feed materials described in the above examples, the combination of the estrogenic substance and the salt of a cationic surfactant were intimately mixed with another feed ingredient such as bone meal or limestone. An appropriate amount of this premix was then distributed throughout the entire feed in a feed mixer.

The growth promotant substances described herein not only speed up the growth of the animal, but also maintain the grade of the animal and improve the efiiciency of feed conversion. This is an important advantage since it makes the growing process economical for animal raisers by requiring less feed per pound of weight gain while producing a high grade animal.

While in the foregoing specification various embodiments of this invention have been set forth and specific details thereof elaborated for the purpose of illustration, it will be apparent to those skilled in the art that the invention is susceptible to other embodiments and that many of these details may be varied widely without departing from the basic concept and spirit of the invention.

We claim:

1. A growth promoting composition of matter comprising a synthetic estrogenic substance and a substantially water-insoluble salt of a cationic surfactant said salt having substantially no surface activity in water.

2. A growth promoting composition of matter comprising a synthetic estrogenic substance and a substantially waterdnsoluble compound composed of a cationic fragment of a cationic surfiactant and the anionic fragment of an anionic surfactant.

3. A composition as claimed in claim 2 in which the estrogenic substance is a stilbene derivative and the cationic surfactant is a quaternary ammonium surfactant.

4. A composition of matter as claimed in claim 3, in

7 which said quaternary ammonium surfactant is a rtrimethyl alkyl ammonium compound in which the alkyl group contains from 8 to 22 carbon atoms.

5. A growth promoting composition of matter comprising a synthetic es-trogenic substance and a substantially water-insoluble compound composed of a cationic frag ment of a cationic surfactant and the anionic fragment of an anionic polyelectrolyte.

6. A composition as claimed in claim 5 in which the estrogenic substance is a stilbene derivative and the cationic surfactant is a quaternary ammonium surfactant.

7. A growth promoting composition of matter comprising a stilbene estrogenic derivative and a substantially water-insoluble salt of a trimethyloctadecylammoniinn surfactant said salt having substantially no surface activity in water.

8. A growth promoting composition of matter comprising diethylstilbestrol and trimethyloctadecylammonium stearate.

9. An animal nutrient material characterized by containing as its essential active ingredient a combination of a synthetic estrogenic substance and a substantially waterinsoluble salt of a cationic surfactant said salt having substantially no surface activity in water.

10. An animal nutrient material characterized by containing as its essential active ingredients :a combination of diethylstilbestrol and trimethyloctadecylammonium stearate.

11. A growth promoting composition of matter comprising a synthetic estrogenic substance and mixtures of substantially water-insoluble salts of cationic surfactants said salts having substantially no surface activity in water.

12. A growth promoting composition of matter comprising diethylstilbestrol and a mixture of trimethylhexadecylammonium stearate and trimethyloctadecylammonium stearate.

13. An animal nutrient material characterized by containing as its essential active ingredients the combination of a synthetic estrogenic substance and mixtures of substantially water-insoluble salts of cationic surfactants said salts having substantially no surface activity in water.

14. A nutrient material characterized by containing as its essential :active ingredients the combination of diethylstilbestrol and a mixture of trimethylhexadccylammonium stearate and trimethyloctadecylammonium stearate.

References Cited in the file of this patent UNITED STATES PATENTS Cunkelman May 1, 1951 Rogers July 22, 1958 OTHER REFERENCES 

1. A GROWTH PROMOTING COMPOSITION OF MATTER COMPRISING A SYNTHETIC ESTROGENIC SUBSTANCE AND A SUBSTANTIALLY WATER-INSOLUBLE SALT OF A CATIONIC SURFACTANT SAID SALT HAVING SUBSTANTIALLY NO SURFACE ACTIVITY IN WATER. 